Early childhood caries (ECC) is the most common chronic disease of childhood and a persistent clinical and public health problem. The prevalence of ECC in the US increased by 15% during the last 2 decades, and according to the most recent national data 28% of children ages 2-5 are affected. ECC can have severe sequelae for children's general health and well-being and confers important social and economic impacts on their families, communities, and the health system. Caries is a multifactorial disease with a substantial genetic component, which is estimated between 40-60% (43% using our own pilot data), but little is known regarding specific genetic factors. To-date, a GWAS of the traditional definition of ECC (including tooth surfaces affected, restored or missing due to dental caries in children younger than 72 months) has not been done. The first GWAS of childhood caries was conducted among 1,300 3-12-year-old European-ancestry children?that study did not identify any significant signals but nominated 7 genes, 2 of which showed evidence of association in follow-up studies among children and adults. A recent GWAS meta-analysis identified one significant locus for childhood caries, among 17,033 children of European ancestry. Here, we propose to conduct a large-scale GWAS of ECC involving a multi-ethnic community-based sample of 6,000 children ages 3 to 5. Under NIH/NIDCR U01-DE025046, we have undertaken comprehensive clinical dental characterization of a community-based sample of over 6,000 children enrolled in Head Start programs in North Carolina. We have obtained tooth-surface level data of dental caries experience using the latest International Caries Diagnosis System (ICDAS) visual diagnostic criteria to define ECC traits. We have obtained saliva samples from virtually all examined participants and have been extracting more-than-adequate DNA yields from them. A wealth of additional behavioral risk factor and socio-demographic information of interest has been collected. Supragingival plaque samples have also been collected and stored to be used in future microbiome analyses that will be funded separately. To identify genetic variants that are associated with ECC, we propose to conduct a trans-ethnic GWAS of ECC and related traits, utilizing high- density genotyping and subsequent imputation to the most current reference panels. We will use advanced statistical approaches to leverage differences in genetic structure between racial/ethnic groups. Subsequently, we will utilize publicly available GWAS data of early childhood and adult caries, to determine the racial/ethnic and age-group generalization/transferability of loci, genes, and gene sets/pathways identified in our study. Our group's experience in conducting genetic epidemiologic studies, ongoing collaboration among the investigators' team and the breadth and quality of the already-collected information, create a unique opportunity to carry out this important investigation and advance the knowledge base of genomics of dental caries. The study will improve our understanding of ECC's genomic etiology, key knowledge to reduce the burden of disease in populations of young children, including those underrepresented in research.